The aims of this study are to advance Type 2 translational science and theory building through targeting risk and protective factors for substance use and sexual risk (e.g., HIV/AIDS) among 8th and 9th grade South African youth. We will focus on factors that influence implementation fidelity of HealthWise South Africa: Life Skills for Adolescents, an evidence-based substance use and sexual risk prevention program that fills an educational vacuum in the high school curriculum at an age when students are at very high risk for initiating substance abuse and sexual risk. HealthWise, which has systematically evolved since 2000 through phases of pilot testing and an efficacy trial, will be disseminated to 56 high schools in South Africa beginning in February 2011. This presents us with an unprecedented opportunity to conduct an innovative randomized experiment to investigate three key independent variables hypothesized to influence implementation fidelity: teacher training; teacher structure, support and supervision; and enhancement of school environment. A cost analysis will also be conducted. Longitudinal outcome and process data will be collected from teachers, principals and students. Because of its scope and innovativeness, this has potential to be a landmark Type 2 translation study that will have implications for other research on school-based prevention programs that attempt to move to scale and translate to conditions that are outside of research-driven contexts. It will also address a critical gap in sexual risk and substance use prevention among South African youth at a particularly vulnerable time.